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EC number: 600-809-4 | CAS number: 1072-53-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Carcinogenicity
Administrative data
Description of key information
Key: Literatue data on 1,3,2-Dioxathiolane, 2,2-dioxide:
In the paper of Van Duuren et al.(1974), ESA (glycol sulfate) was tested in female ICR/Ha Swiss mice for carcinogenic activity.
Routes of administration No of mice / group |
Dose or volume / solution |
Application site |
Treatment frequency / duration |
Outcome |
skin n = 30 |
0.1 mg/0.1 mL acetone |
interscapular region (shaved skin) |
3 times a week / 456 days |
No papilloma / no carcinoma Summary: 0/30 |
sc injection n = 30 |
0.5 mg/0.05 mL tricaprylin |
left flank |
once a week / 413 days |
21 sarcomas / 1 squamous cell carcinomas / 0 adenocarcinomas (P for total malignant tumors < 0.01 : significant tumorogenic activity) Summary: 22/30 |
ip injection n = 30 |
0.05 mg/0.05 mL tricaprylin |
lower abdomen |
once a week / 450 days |
9 papillary tumors of lung / 5 local sarcomas Summary: 6/30 |
The authors carefully regarded the test item solubility and stability before testing: ESA was diluted in acetone or tricaprylin. ESA diluted in acetone showed no more than 1% degradation during a month.
ESA tested though subcutaneous (sc) injection showed significant local malignant tumor incidence (P < 0.01) of sarcomas at the injection site. Authors assumed that the sulfate reacting with nucleophiles in neutral media undergoes C-O scission. In these instances, one requirement for biologic activity seems to be ready cleavage of the carbon-oxygen bond.
In the described test, no local and distant tumours were observed after the mouse skin application with 0.1 mg ESA/ 0.1 mL acetone 3 times a week during 456 days. In addition, no skin tumours after similar exposure were observed in an open chain analogue dimethyl sulfate. It can therefore be assumed that dermal exposure to ESA at the indicated level was the Non Observed Effect Level (NOEL) related to the absence of tumour incidence. However, no other information related to the other adverse toxicity in mice after ESA exposure was available.
Supporting literature data on structurally similar substances:
1,3-propanesultone (EC 214-317-9, CAS 1120-71-4):
Druckrey et al, 1970:
According to the literature (Druckrey et al, 1970), 1,3-propanesultone is highly reactive and is rapidly destroyed by heterolysis (half-life of hydrolyse t1/2was 110 min at 37 °C in phosphate buffer with pH 7.4). When given sc at weekly dosages of 15 and 30 mg/kg bw respectively, and even as single dose, it produces a high yield of sarcomas at the site of injection. After oral or intravenous (iv) administration only a limited number of malignant tumours in remote organs is observed, 10 of them in the nervous system. When given to pregnant rats on the 15thday of gestation as a single iv injection of 20 and 60 mg/kg respectively, malignant and mainly neurogenic tumours occurred in 7 out of 39 rats of the offspring. According to these results, 1,3-propanesultone is a potent carcinogen. The next higher homologue, 1,4-butanesultone is much less carcinogenic and may account for this difference in the structure and biological activity.
Weisburger et al, 1981:
Fourteen chemicals, including propane sultone, were tested for carcinogenicity by oral administration in male and female Charles River CD rats.
Propane sultone induced significant increases in malignant gliomas and mammary adenocarcinomas, and the incidences of leukemia, cancer of the small intestine, and squamous cell carcinoma of the ear duct were increased over those in controls.
Under the conditions of the test, propane sultone, in addition to the positive control (N-2-fluorenylacetamide), were carcinogenic.
Methyl methanesulphonate (EC 200-625-0, CAS 66-27-3):
Sekkakumar et al, 1987:
Inhalation exposure was conduct on water reactive compound, methylmethane sulfonate (MMS), on male Sprague-Dawley rats. The comound was administered for 30 days (6 hr/day x 5 days/wk) with the use of exposure concentrations that were inversely proportional to hydrolysis rate: t1/2: 580 min, exposure concentraiton 50 ppm.
Within this protocol, MMS produced nasal cancer in rats. The concentration of MMS employed in the studies produced similar nasal cancer yields, indicating that the carcinogenic potency of this compound in rat nasal mucosa was proportional to this hydrolysis rate.
Dimethyl sulfate (EC 201-058-1, CAS 201-058-1)
According to literature, subcutaneous injections once a week of dimethyl sulfate produced local sarcomas in BD-strain rats, the yield corresponding to dosage. However, given by oral route or by intravenous injections dimethyl sulfate was inactive. Inhalation of dimethyl sulfate vapours, 3 and 10 ppm respectively for one hour five times per week, however, produced squameous carcinomas of the nascal cavity or neurogenic tumours in 8 out of 27 exposed rats.
The substances used for supporting data are all classified for carcinogenicity and are described as alkylating agents.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Mode of Action Analysis / Human Relevance Framework
The substance has been identified as a possible alkylating agent in available literature data and by QSAR structural alerts. However, the mode of action is not able to be definitively concluded from the available data.
Justification for classification or non-classification
Based on the available data the substance, 1,3,2-Dioxathiolane, 2,2-dioxide is classified as Carc. Cat 2 (H351: Suspected of causing cancer).
No route of exposure is identified as the available literature data on ESA, showing significant local malignant tumor incidence, was by exposure through subcutaneous (sc) injection.
Insufficient data is available on oral, inhalation and dermal exposure routes on 1,3,2-Dioxathiolane, 2,2-dioxide
to conclusively prove that there is no hazard via any of these routes.
Additional information
ESA QSAR modelling: carcinogenicity and carcinogenic potency TD50:
Further investigation of ESA carcinogenic properties by means of (Q)SAR modelling was performed.
The carcinogenicity of ESA was investigated by in silico modelling. From a qualitative point of view two highly reliable predictions were positive in RFMN/Antares and IRFMN/ISSCAN-CGX models. With low reliability, positive weight of evidence for carcinogenicity in rodents was predicted by TOPKAT.
The OECD QSAR Toolbox profiled the query compound according to oncologic primary classification as well as OncoLogic™ software for sultone reactive group alert. Sultones are direct-acting alkylating agents. However, in the OECD QSAR Toolbox there was not enough data to conduct the read across analysis with proposed structural similar compounds.
Performed (Q)SAR modelling with ESA hydrolysis product, hydroxyethyl sulphate, showed in the predictions less expressed carcinogenic properties. As for ESA, two out of four Vega carcinogenicity models predicted hydroxyethyl sulphate to be carcinogen showing high and moderate reliabilities. All negative predictions for hydroxyethyl sulphate were low reliable (Caesar, ISS; TOPKAT). In addition, no alert was triggered in the OECD QSAR Toolbox according to oncologic primary classification as well as in OncoLogic™ software.
In the TOPKAT modelling the TD50 standardized measure of carcinogenic potency was used. TD50 is the daily dose rate in mg/kg bw/day to induce tumors in half of test animals that would have remained tumor-free at zero dose. The carcinogenic potency TD50 for ESA was 3 and 7 times lower than for its hydrolysis product hydroxyethyl sulphate in mouse and rat, respectively. The reduction of carcinogenic potency in the hydrolysis product correlates with the lower evidence of carcinogenicity of hydroxyethyl sulphate in the carcinogenicity predictions of the (Q)SAR models.
This tendency is also observed by analogue structure 1,3‑propanesultone where the carcinogenic potency TD50 modelled with TOPKAT, for 1,3‑propanesultone was 2 and 6 times lower than for 3-hydroxypropane-sulophonic acid.
ESA (Q)SAR modelling
Carcinogenicity Model |
Prediction |
Reliability |
VEGA |
|
|
-Caesar |
neg |
low |
-ISS |
neg |
low |
-RFMN/Antares |
pos |
high |
-IRFMN/ISSCAN-CGX |
pos |
high |
Toxtree |
no alert |
- |
OECD QSAR Toolbox |
|
|
-Oncologic Primary Classification |
Alert: sultone reactive functional group |
- |
-Carcinogenicity (gentox and nongenotox) alerts by ISS |
no alert |
- |
OncoLogic |
pos |
low |
TOPKAT |
|
|
-Weight of evidence |
pos |
low |
-Carc Potency TD50 mouse (mg/kg bw/day) |
40.2 |
low |
-Carc Potency TD50 rat (mg/kg bw/day) |
28.8 |
low |
Hydrolysis product: Hydroxyehtyl sulphate (Q)SAR modelling:
Carcinogenicity Model |
Prediction |
Reliability |
VEGA |
|
|
-Caesar |
neg |
low |
-ISS |
neg |
low |
-RFMN/Antares |
pos |
mod |
-IRFMN/ISSCAN-CGX |
pos |
high |
Toxtree |
no alert |
- |
OECD QSAR Toolbox |
|
|
-Oncologic Primary Classification |
no alert |
- |
-Carcinogenicity (gentox and nongenotox) alerts by ISS |
no alert |
- |
OncoLogic |
N/A |
low |
TOPKAT |
|
|
-Weight of evidence |
neg |
low |
-Carc Potency TD50 mouse (mg/kg bw/day) |
123.8 |
low |
-Carc Potency TD50 rat (mg/kg bw/day) |
207.6 |
low |
QSAR modelling was also performed on 1,3-propanesultone (which has a harmonised classification for carcinogenicity) to compare against the QSAR modelling results for ESA.
Positive results for carcinogenicity were also obtained for 1,3 -propansultone.
1,3-propanesultone (Q)SAR modelling
Carcinogenicity Model |
Prediction |
Reliability |
VEGA |
|
|
-Caesar |
neg |
low |
-ISS |
pos |
high |
-RFMN/Antares |
pos |
high |
-IRFMN/ISSCAN-CGX |
pos |
high |
Toxtree |
Alert: propiloactones/propiosultones |
- |
OECD QSAR Toolbox |
|
|
-Oncologic Primary Classification |
Alert: sultone reactive functional group |
- |
-Carcinogenicity (gentox and nongenotox) alerts by ISS |
Alert: propioloactones or propiosultones (genotox) |
- |
OncoLogic |
pos |
- |
TOPKAT |
|
|
-Weight of evidence |
pos |
mod |
-Carc Potency TD50 mouse (mg/kg bw/day) |
40.1 |
low |
-Carc Potency TD50 rat (mg/kg bw/day) |
31.1 |
high |
Lower evidence of carcinogenicity of 3-hydroxypropane-sulophonic acid (hydrolysis product) was observed when compared against 1,3 -propanesultone.
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